The human adult skeleton undergoes continuous remodeling, a delicate balance between bone formation by the osteoblast and bone resorption by the osteoclast. Intermittent administration of parathyroid hormone (PTH) is able to greatly stimulate bone formation by acting through its receptor on the osteoblast. Recently, I, in Dr. Nicola Partridge's laboratory, identified that amphiregulin, an epidermal growth factor (EGF)-like ligand, is strongly upregulated by PTH in the osteoblast and that the EOF signaling pathway plays an important role in normal bone development. Although EGF-like ligands and their signaling pathways have been extensively studied in many tissues and cancers, there are few reports of them in the skeletal field due to the lack of evidence that they are expressed in bone and that they participate in remodeling. From my preliminary data, I hypothesize that EGF signaling participates in regulating the proliferation and differentiation of mesenchymal cell lineages, such as osteoblasts, adipocytes and chrondrocytes, and that PTH uses amphiregulin as the mediator to manipulate the microenvironment of bone marrow stromal stem cells. Thus, the goal of the present application is to delineate the role of EGF-like ligands, especially amphiregulin, in bone metabolism and in PTH's action on bone. To achieve it, I will use the following approaches: 1. Identifying amphiregulin target cells in bone and investigating how PTH treatment affects these cells, 2. Studying the effect of amphiregulin on the proliferation and differentiation of stromal stem cells, 3. Examining the physiological role of amphiregulin signialing in bone development and in PTH's action using animal models. The results of this work will provide insight into a novel and potentially important signaling pathway in bone development and metabolism and its role in PTH's action on bone.